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Transl Psychiatry

Title:		A novel rat model of comorbid PTSD and addiction reveals intersections between stress susceptibility and enhanced cocaine seeking with a role for mGlu5 receptors
Author(s):		Schwendt M; Shallcross J; Hadad NA; Namba MD; Hiller H; Wu L; Krause EG; Knackstedt LA;
Address:		"Psychology Department, University of Florida, Gainesville, FL, 32611, USA. schwendt@ufl.edu. Center for Addiction Research and Education, University of Florida, Gainesville, FL, 32610, USA. schwendt@ufl.edu. Psychology Department, University of Florida, Gainesville, FL, 32611, USA. Department of Pharmacodynamics, University of Florida, Gainesville, FL, 32610, USA. Center for Addiction Research and Education, University of Florida, Gainesville, FL, 32610, USA"
Journal Title:		Transl Psychiatry
Year:		2018
Volume:		20181005
Issue:		1
Page Number:		209 -
DOI:		10.1038/s41398-018-0265-9
ISSN/ISBN:		2158-3188 (Electronic) 2158-3188 (Linking)
Abstract:		"PTSD is highly comorbid with cocaine use disorder (CUD), and cocaine users with PTSD + CUD are more resistant to treatment. Here we sought to develop a rat model of PTSD + CUD in order to identify the neurobiological changes underlying such comorbidity and screen potential medications for reducing cocaine seeking in the PTSD population. We utilized a predator scent stress model of PTSD, wherein rats received a single exposure to the fox pheromone 2,5-dihydro-2,4,5-trimethylthiazoline (TMT). One week after TMT exposure, stress-susceptible (susceptible), intermediate, and resilient phenotypes were detected and were consistent with behavioral, corticosterone, and gene expression profiles 3 weeks post TMT. We assessed phenotypic differences in cocaine self-administration, extinction, and cue-primed reinstatement. Susceptible rats exhibited deficits in extinction learning and increased cue-primed reinstatement that was not prevented by Ceftriaxone, an antibiotic that consistently attenuates the reinstatement of cocaine seeking. TMT-exposed resilient rats displayed increased mGlu5 gene expression in the amygdala and medial prefrontal cortex and did not display the enhanced cocaine seeking observed in susceptible rats. Combined treatment with the mGlu5 positive allosteric modulator 3-Cyano-N-(1,3-diphenyl-1 H-pyrazol-5-yl)benzamide (CDPPB), fear extinction, and ceftriaxone prevented the reinstatement of cocaine seeking in susceptible rats with fear extinction an important mediating condition. These results highlight the need for animal models of PTSD to consider stress-responsivity, as only a subset of trauma-exposed individuals develop PTSD and these individuals likely exhibit distinct neurobiological changes compared with trauma-exposed populations who are resilient to stress. This work further identifies glutamate homeostasis and mGlu5 as a target for treating relapse in comorbid PTSD-cocaine addiction"
Keywords:		"Animals Anxiety Behavior, Animal Brain/drug effects/metabolism Cocaine/administration & dosage Cocaine-Related Disorders/*complications/metabolism Comorbidity *Disease Models, Animal *Drug-Seeking Behavior Extinction, Psychological/drug effects Fear Male;"
Notes:		"MedlineSchwendt, Marek Shallcross, John Hadad, Natalie A Namba, Mark D Hiller, Helmut Wu, Lizhen Krause, Eric G Knackstedt, Lori A eng R01 DA033436/DA/NIDA NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. 2018/10/07 Transl Psychiatry. 2018 Oct 5; 8(1):209. doi: 10.1038/s41398-018-0265-9"